Novel insights into GPCR-peptide interactions: mutations in extracellular loop 1, ligand backbone methylations and molecular modeling of neurotensin receptor 1

Bioorg Med Chem. 2008 Oct 15;16(20):9359-68. doi: 10.1016/j.bmc.2008.08.051. Epub 2008 Aug 27.


Investigating prototypical interactions between NT(8-13) and the human neurotensin receptor 1 (hNTR1), we created a receptor-ligand model that was validated by site-directed mutagenesis and structure-activity relationship studies. Stabilization of the extracellular loop 1 (EL1) by pi-stacking clusters proved to be important for agonist binding when substitution of six conserved amino acids by alanine resulted in an agonist specific loss of maximal binding capacity. In agreement with our modeling studies, EL1 seems to adopt a clamp-type border area controlling the shape of the binding site crevice. Employing chemically manipulated peptide analogs as molecular probes, the impact of backbone modifications on receptor-ligand interaction, especially the influence on ligand conformation, was examined in binding studies and explained by in silico analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Computer Simulation
  • Humans
  • Ligands
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Peptides
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Neurotensin / chemistry*
  • Receptors, Neurotensin / genetics
  • Receptors, Neurotensin / metabolism*
  • Sequence Alignment


  • Ligands
  • Peptides
  • Receptors, Neurotensin
  • neurotensin type 1 receptor